Osteocytes are terminally differentiated osteoblasts that are imbedded in the bone matrix and are thought to initiate the skeletal response to mechanical strain. Recently, osteocytes have been implicated in the control of systemic mineral homeostasis and in regulating the rate of bone formation. However, the signal transduction pathways that regulate the biological function of osteocytes are poorly defined. Limited evidence suggests an important role for the stimulatory G protein (Gs)/cAMP pathway in osteocyte function. Cyclic AMP signaling in osteocytes appears to synergize with the effects of mechanical loading, suggesting the existence of common downstream targets. Moreover, cAMP signaling in osteocytes down-regulates the expression of the gene encoding sclerostin, an effect that could mediate the anabolic response of the skeleton to agents such as parathyroid hormone (PTH) and PGE2, the receptors for which are present on osteocytes and are coupled to activation of the Gs/cAMP pathway. In the present study, we propose to explore the hypothesis that PKA activation in osteocytes plays a key role in controlling bone formation. To test this hypothesis, we will use a genetic approach to manipulate PKA activity selectively in osteocytes in vivo. Specifically we will: 1) determine whether activation of PKA in osteocytes is sufficient to drive increased bone formation. To accomplish this, we will employ mice harboring a Cre-conditional, mutated PKA catalytic subunit allele that allows expression of constitutively active PKA activity in osteocytes. The effects of activated osteocyte PKA on skeletal homeostasis in growing and mature mice will be assessed;2) determine whether dampening of PKA activity in osteocytes suppresses bone formation. To accomplish this, we will employ mice harboring a Cre-conditional allele for a mutated PKA regulatory subunit that allows expression in osteocytes of PKA that is resistant to activation by cAMP. The effects of reduced responsiveness of osteocyte PKA on skeletal homeostasis in growing and mature mice will be assessed;and 3) assess the role of PKA activation in osteocytes in mediating the anabolic response of the skeleton to intermittent administration of PTH. This will be accomplished by testing the anabolic response to PTH in mice that express a cAMP-resistant form of PKA in osteocytes. PTH has been approved for use in the treatment of osteoporosis but its beneficial effects are limited. Better understanding of PKA signaling in osteocytes would help define the basis of the anabolic effects of PTH and could lead to the identification of new therapeutic targets for the treatment of osteoporosis and related osteopenic diseases.